Transcript nucleophile (亲核试剂)

Chapter 6 Reactions of Carbonyl Compounds
羰基化合物的反应
6-1 Nucleophilic Addition Reacitions亲核加成反应
6-2 Nucleophilic Addition-Elimination Reactions 亲
核加成消除反应
6-3 Condensation Reactions 缩合反应
6-4 The Nucleophilic Substitutions of Carbonyl
Acid and Their Derivatives 羧酸及其衍生物的亲核
取代
Key Terms Involved in This Chapter
carbonyl (羰基)
aldehyde(醛)
ketone (酮)
nucleophilic(亲核的) nucleophile (亲核试剂)
electrophilic (亲电的) electrophile(亲电试剂)
carbanion（碳负离子）
diastereomer （非对映体）
Introduction
Several functional groups contain the carbonyl group.
Structure
of the Carbonyl Group
The carbonyl carbon is sp2 hybridized and is trigonal
planar. All three atoms attached to the carbonyl group
lie in one plane.
The carbonyl group is polarized.
There is substantial d+ charge on the carbon.
nucleophilic
at oxygen
.. dO:
C
electrophiles
add here
H+ or E+
.. :O :
d+
C
electrophilic
at carbon
Nu:
+
nucleophiles
attack here
Nu: nucleophile 亲核试剂
6-1 Nucleophilic Addition Reactions（亲核加成反应）
Carbonyl groups can undergo nucleophilic addition.
The nucleophile adds to the d+ carbon.
The  electrons shift to the oxygen.
The carbon becomes sp3 hybridized and therefore
tetrahedral.
Mechanisms in Basic or Neutral Solutions
.. _
: O:
..
O:
C
slow
+
:Nu
C
An alkoxide ion
Nu
.. _
: O:
..
:O H
fast
C
Nu
+
H2O
or adding acid
C
Nu
An alcohol
A strong nucleophile attacks the carbonyl carbon,
forming an alkoxide ion that is then protonated.
 Acid
Catalyzed Mechanisms
+
:O
..
O:
C
+
+
H
fast
more reactive to
addition than the unprotonated precursor
C
..
:O
.. +
O H
H
slow
+
C
H
:Nu
C
Nu
Acid catalysis speeds the rate of addition of weak nucleophiles and
weak bases (usually uncharged).
ACIDIC SOLUTION pH 5-6
stronger acid protonates the
nucleophile
Typical Nucleophilies
Nu-: -CN, CC-, RMgX, RLi, RZnBr,
Witting Reagents, H-, -OH, RO-, HSO3-,
Nu: H2O, ROH, RNH2, NH2OH, H2NNHR
1. Cyanides act as nucleophiles toward C=O
.. _
:O :
Buffered to pH 6-8
:O :
_
R
C
R
+
CN
R
C
R
CN
.. _
:O :
R
C
CN
..
:O
R
+
H2O
R
C
H
R
CN
a cyanohydrin
In acid solution there would be little CN-,
and HCN (g) would be a problem (poison).
(1) Reactivity of Aldehydes and Ketones
H
C
H
O
>
CH3
C
O
H
formaldehyde acetaldehyde
>
R
CH3
C
CH3
acetone
O
>
Ar
C
CH3
O
>
C
CH3
Methyl ketones
Aldehydes are generally more reactive than ketones
in nucleophilic additions.
O
(2) Factors affecting the nucleophilic addition
Electronic effects of alkyl groups
R
R
¦Ä+
C O
¦Ä+
C O
H
H
Nu Electron-donating group
makes C=O less electrophilic
less reactive
Nu Electron-withdrawing group
makes C=O more electrophilic
more reactive
K =210
CHO
HCN
CHO
Br
K=530
HCN:
hydrocyanic acid
Steric effect
Hybridization: sp2 sp3
The bond angle:
120° 109.5°
R
R/(H)
C
O
CH3
C
O
K
HCN
CH3CH2
>
(CH3)3C
C
O
K<< 1
(CH3)3C
The crowding in the products is increased
by the larger group
1
(3) Sterochemistry
Watch out for the possibility of optical isomerism in hydroxynitriles
CN¯ attacks from above
CN¯ attacks from below
Enantiomers
CN¯ attacks
from above
Enantiomers
CN¯ attacks
from below
Cram’s Rule
*
C
X
非对映体
diastereomeric
X = C, O, N
Chiral
center
How does this center control the direction of
attack at the trigonal carbon?
S
O
M
L
LR
Less steric
Nu:
Nu
L
S
R
M
OH
Major product
S
R
O
Perspective drawing
More steric
Nu:
M
R
L
Nu
M
OH
Minor product
S
2. Grignard reagents act as nucleophiles toward C=O
Grignard reagents are prepared
by the reaction of organic halides
with magnesium turnings
Aldehydes and ketones react with Grignard reagents to
yield different classes of alcohols depending on the starting
carbonyl compound
Esters react with two molar equivalents of a Grignard reagent to
yield a tertiary alcohol
A ketone is formed by the first molar equivalent of Grignard reagent
and this immediately reacts with a second equivalent to produce the alcohol.
The final product contains two identical groups at the alcohol carbon
that are both derived from the Grignard reagent.
Planning a Grignard Synthesis
Example : Synthesis of 3-phenyl-3-pentanol
Restrictions on the Use of Grignard Reagents
Grignard reagents are very powerful nucleophiles and bases.
They react as if they were carbanions.
Grignard reagents cannot be made from halides which contain
acidic groups or electrophilic sites elsewhere in the molecule.
The substrate for reaction with the Grignard reagent
cannot contain any acidic hydrogen atoms.
Two equivalents of Grignard reagent could be used, so that
the first equivalent is consumed by the acid-base reaction ,
while the second equivalent accomplishes carbon-carbon
bond formation.
Sterochemistry-Cram’s rule
O
H
Ph
H
C2H5
1 RMgX
C2H5
2 H2O
H
PhH
O
R
OH
C2H5
H
H
OH
C2H5
H
+
H
R
Ph
Ph
Ph
H
HO
R
major
Ph
C2H5
H
C2H5
H
H
OH
R
minor
R
CH3
C 6 H5
(CH3)2CH
(CH3)3C
major minor
2.5 :
1
> 4
:
1
5 :
1
49 :
1
3. Organolithium act as nucleophiles toward C=O
Organolithium reagents react with aldehydes and
ketones in the same way that Grignard reagents do.
4. Sodium alkynides act as nucleophiles toward C=O
NaNH2: sodium amide
propine
Sodium alkynide
5. Reformatskii Reactions (Organozinc Addition to C=O )
¦Á-bromoester
R
OZnBr
C=O + Br-C-CO2R + Zn
(R)H
C-CO2R
C
R
(R)H
BrZn-C-CO2R
OH
+
H3O
C
R
C-CO2R
(R)H
¦Â-hydroxyester
Organozinc is not as reactive as Grignard reagent,
so it will not reactive with esters
Br
C2H5CHCHO + CH3-CH-CO2C2H5 + Zn
C4H9(n)
+
H3O
OH CH
3
C2H5CHCH -CH-CO2C2H5
C4H9(n)
6. Wittig reaction (Ylides addition to C=O )
Synthetic method for preparing alkenes.
A compound or intermediate with both a
positive and a negative charge on
adjacent atoms.
- ..
Ylide
X
+
Y
BOND
Betaine or Zwitterion
内铵盐
A compound or intermediate with
both a positive and a negative charge,
not on adjacent atoms, but in different
parts of the molecule.
两性离子
+
MOLECULE
-:
X
Y
R
C
••
+
(C6H5)3P
+
O
••
–
C ••
B
R'
R
A
C
A
+
C
B
R'
An alkene
•• –
O ••
••
triphenyl phosphine oxide
+
(C6H5)3P
（三苯基氧膦）
Preparation of a Phosphorous Ylide
( WITTIG REAGENT )
phosphonium salt
Substrates: 1°, 2°Alkyl halides
R2
R1
C
X
+
H
(C6H5)3P :
benzene
R1
+
(C6H5)3P
C
R2
H
SN2 reaction
- ..
ether
strong base
Ph
Triphenylphosphine
( Ph = C6H5 )
X
: O-CH
3
..
..
Ph P Ph
_
+
(C6H5)3P
- ..
an ylide
R1
C
R2
The Wittig Reaction
MECHANISM
R1
C
O +
-..
+
(C6H5)3P
R3
C
R2
R4
R2
ylide
betaine
R1
R3
C
C
: O:
.. _
R4
P(C6H5)3
+
内磷盐
R1
R3
C
R2
+
C
R4
synthesis of
an alkene
O
P(C6H5)3
INSOLUBLE
very thermodynamically
stable molecule
R2
R1
R3
C
C
:O
..
R4
P(C6H5)3
oxaphosphetane
(UNSTABLE)
SYNTHESIS OF AN ALKENE - WITTIG REACTION
H3C
CH2CH3
H3C
Br
CH2CH3
O
H3C
H3C
H
H
H
H3C
:P(C6H5)3
O
H3C
+
+
(C6H5)3P CH2CH3
ylide
-
:
H
(C6H5)3P
CH3ONa
H
CH2CH3
H
ANOTHER WITTIG ALKENE SYNTHESIS
H
+
Br
C P(C6H5)3
CH2Br
H
:P(C6H5)3
PhLi
H
C
H
O
C P(C6H5)3
..
-
+
ylide
+
..
P(C6H5)3
:O
..
+
Br
C
triphenylphosphine
oxide (insoluble)
H H
O
Synthesis of β-Carotene （β-胡萝卜素）
2
CH P(C6H5)3
+ O CH
Georg F. K. Wittig received the Nobel Prize
in Chemistry in 1979.
CHO
German chemist whose method of
synthesizing olefins (alkenes) from carbonyl
compounds is a reaction often termed the
Wittig synthesis. For this achievement he
shared the 1979 Nobel Prize for Chemistry.
In the Wittig reaction, he first
demonstrated 1954, a carbonyl compound
(aldehyde or ketone) reacts with an organic
phosphorus compound, an alkylidenetriphenylphosphorane, (C6H5)3P=CR2,
where R is a hydrogen atom or an organic
radical. The alkylidene group (=CR2) of the
reagent reacts with the oxygen atom of the
carbonyl group to form a hydrocarbon with
a double bond, an olefin (alkene).
The reaction is widely used in
Georg Wittig
organic synthesis, for example to make
1/2 of the prize
University of Heidelberg squalene (the synthetic precursor of
Heidelberg, Federal
cholesterol) and vitamin D3
Republic of Germany
b. 1897
d. 1987
7. Hydride Addition to C=O
LiAlH4, NaBH4, AlH3
OH
O
1) "H
R
"
H or R'
R
H or R'
2) H
NaBH4, NADH (with dehydrogenase)
H
"H
HOH orHOR
"
O
R
H or R'
Sources of hydride ("H-"), such as NaBH4, LiAlH4, all convert aldehydes and
ketones to the corresponding alcohols by nucleophilic addition of hydride to C=O,
followed or concurrently with protonation of the oxygen
C2H5
H
C6H5
LiAlH4
O
C
C
H2 O
Ethyl ether
CH3
C2H5
H
OH
H
C
C
CH3
C6H5
75%
C2H5
H
+
H
OH
C
C
CH3
C6H5
25%
H3C
CH3
O
H3C
CH3
H3C
CH3
NaBH4
OH
H
OH
H
80%
20%
Steric Hindrance to Approach of Reagent
this methyl group hinders
approach of nucleophile
from top
–
H3B—H
preferred direction of
approach is to less hindered
(bottom) face of carbonyl group
Biological reductions are highly stereoselective
pyruvic acid
S-(+)-lactic acid
CO2H
O
CH3CCO2H
NADH
HO
H
H+
CH3
enzyme is lactate dehydrogenase
One face of the
substrate can bind to
the enzyme better
than the other.
Change in geometry from trigonal to tetrahedral is
stereoselective. Bond formation occurs
preferentially from one side rather than the other.
8. Hydration of C=O
OH
H or OH
(catalyst)
O
R
R
H or R'
HOH
H or R'
OH
hydrates or gem-diols
OH
H or OH
(catalyst)
O
(100%)
H
H
H
HOH
OH
OH
H or OH
(catalyst)
O
H
(58%)
H3C
H
HOH
H3C
H
OH
steric hindrance in the product
Very electrophilic C=O carbon because of nearby highly electronegative atoms
OH
H or OH
(catalyst)
O
R
R
H or R'
HOH
H or R'
OH
R = CH2X, CHX2, CX3 (X = F, Cl, Br); R = R' = CH2X
favorable
H
Cl3C
..
C=O + H-OH
H
Cl3C
C
OH
OH
Knock out drops
O
O
O + H2O
H
O
O
O
O H
Hydrate formation relieves some ring strain
by decreasing bond angles
O
H or OH
(catalyst)
HOH
HO
OH